Implementation of targeted cholera response activities, Cameroon

Abstract Objective To describe the implementation of case-area targeted interventions to reduce cholera transmission using a rapid, localized response in Kribi district, Cameroon. Methods We used a cross-sectional design to study the implementation of case-area targeted interventions. We initiated interventions after rapid diagnostic test confirmation of a case of cholera. We targeted households within a 100–250 metre perimeter around the index case (spatial targeting). The interventions package included: health promotion, oral cholera vaccination, antibiotic chemoprophylaxis for nonimmunized direct contacts, point-of-use water treatment and active case-finding. Findings We implemented eight targeted intervention packages in four health areas of Kribi between 17 September 2020 and 16 October 2020. We visited 1533 households (range: 7–544 per case-area) hosting 5877 individuals (range: 7–1687 per case-area). The average time from detection of the index case to implementation of interventions was 3.4 days (range: 1–7). Oral cholera vaccination increased overall immunization coverage in Kribi from 49.2% (2771/5621 people) to 79.3% (4456/5621 people). Interventions also led to the detection and prompt management of eight suspected cases of cholera, five of whom had severe dehydration. Stool culture was positive for Vibrio cholerae O1 in four cases. The average time from onset of symptoms to admission of a person with cholera to a health facility was 1.2 days. Conclusion Despite challenges, we successfully implemented targeted interventions at the tail-end of a cholera epidemic, after which no further cases were reported in Kribi up until week 49 of 2021. The effectiveness of case-area targeted interventions in stopping or reducing cholera transmission needs further investigation.


Introduction
Cholera is an infectious disease which causes acute watery diarrhoea as a result of ingestion of water or food contaminated with Vibrio cholerae. 1-3 Cholera remains a global health challenge with the greatest burden in Africa. 2 For severe cases and without timely treatment, cholera quickly causes severe dehydration and death. 4 Within a short period following the emergence of a cholera case in a community, there is an increased risk of cholera among household contacts, [5][6][7] neighbours and people living within a range of 100-250 metres of the infected person. 8,9 Case-area targeted interventions refer to interventions in neighbourhoods of people with cholera, which may include health promotion, oral cholera vaccination, point-of-use water treatment and antibiotic chemoprophylaxis. 10 There is scarce evidence of the effectiveness of targeted interventions in the control of cholera epidemics. A modelling study of targeted interventions (oral cholera vaccination, antibiotics and pointof-use water treatment) observed a reduction in cholera transmission when used as a complement to other interventions. 11 A relationship was observed between the speed of implementing targeted interventions (without oral cholera vaccination) and a reduction in the incidence of suspected cholera cases and of outbreak duration in Haiti from 2015-2017. 10 In Africa, the feasibility of targeted interventions without oral cholera vaccination was described in the Democratic Republic of Congo, in South Sudan [11][12][13][14] and in Cameroon. 15 Targeted spatiotemporal interventions implemented in the neighbourhood of cholera patients in 2004 in Douala, Cameroon, were followed by a reduction in the incidence of cholera among contacts of cases. 15 Case-area targeted interventions have shown promising results regarding cholera outbreak control. 16 In May 2020 (week 18), a cholera epidemic started in the Kribi health district in the South Region of Cameroon. 17 By August 2020 (week 31), a full cholera response was in place. The interventions included: free-of-charge case management; strengthening surveillance; risk communication and community engagement; water, sanitation and hygiene activities (water quality tests, disinfection of households); and a reactive, mass oral cholera vaccination campaign in one health area (week 32) with extension to four health areas (week 36). 18 Despite these interventions, clusters of cases were still reported, especially in slums and at the central prison where oral cholera vaccination coverage was suboptimal. 19 These outbreaks prompted implementation of a rapid, localized response. Given the lack of operational research on case-area targeted interventions, we aimed to describe how targeted interventions with oral cholera vaccination were systematically implemented as complementary interventions to halt the spread of the cholera epidemic in Kribi.

Setting and population
Kribi is a cosmopolitan, seaside town located in the South Region of Cameroon, a major tourist centre. Kribi health district consists of 11 health areas with a population of 154 370 inhabitants. 18 The target population for the study included all people living within a specified radius of an index cholera case, with the radius depending on the population density. For oral cholera vaccination, all persons aged at least 1 year old were eligible. We implemented case-area targeted interventions in Kribi over a period of 1 month from 16 September 2020 (week 38) to 17 October 2020 (week 42).

Strategy
We used a multistage implementation strategy. Stage 1 consisted of preparedness for case-area targeted interventions which was triggered after a report of at least one case of acute watery diarrhoea who tested positive for cholera by enriched rapid diagnostic test. 20 Enrichment of stool specimen with alkaline peptone water increases specificity by up to 97% 20 and reduced the likelihood of obtaining false-positive results. 21 We tested stool samples using rapid diagnostic test kits Crystal® VC (Cholkit, Arkray Health Care Pvt. Ltd, Mumbai, India) or SD Bioline Cholera Ag (Standard Diagnostics Inc., Gyeonggi-do, Republic of Korea). For confirmation, we sent Cary-Blair swab samples to the national public health laboratory in the capital city, Yaounde, for culture as part of an ongoing study on the performance of cholera rapid diagnostic tests.
Stage 2 was the launch of case-area targeted interventions within 7 days after identification of a cholera case confirmed by enriched rapid diagnostic testing. We informed community leaders before we started any activities in the community and asked them to approve all activities to be undertaken.
The main elements of the approach included rapid deployment of a team who visited the household of the index case and discussed the interventions with community leaders. Using a global positioning system (GPS)-enabled tablet computer, the team identified the GPS coordinates of households hosting cholera cases and determined the radius required for the interventions. Field staff also enumerated households and inhabitants before interventions started. Active case-finding involved a search for other people with symptoms of cholera in the same household and in households within the target-area radius. When other cases were detected, the patient was offered oral rehydration solution and referred to the cholera treatment unit in Kribi district hospital if the person was moderately or severely dehydrated.
Stage 3 involved administering interventions in the household of the index case and other households within the target area. In the index household, the interventions included health promotion, water, sanitation and hygiene measures, vaccination and prophylactic antibiotic therapy. The health promotion component comprised education on basic hygiene measures and actions to be taken in case of diarrhoea. The water, sanitation and hygiene intervention included an assessment of the community water source and the availability of toilets; distribution of a minimum number of two packs of chlorine tablets for water purification and five soap bars (350 g) for a period of 1 month; and distribution of water storage containers, where possible. We administered oral cholera vaccination with a single dose of Euvichol® (uBiologics, Seoul, Republic of Korea) to all inhabitants of the household aged at least 1 year old who had not been vaccinated during the mass campaign. Prophylactic antibiotic therapy was designed to reduce the household members' risk of developing severe clinical forms of cholera and to rapidly reduce onward transmission. We offered an oral antibiotic (azithromycin or doxycycline) to all people in the household aged at least 1 year old and who had no history of administration of oral cholera vaccination. We used a door-to-door strategy to deliver interventions to households within the target radius. We offered the same package of interventions (except for antibiotic prophylaxis) to households and residents residing within a radius of 100 to 250 m around the household of the index case, depending on the population density.

Teams and resources
Each case-area targeted interventions team comprised an epidemiologist, an investigator, a water, sanitation and hygiene specialist, a health promotion supervisor and community relay agents who were all national staff from Médecins Sans Frontières and the Cameroon Ministry of Public Health. Depending on the size of the targeted population, the number of community health workers varied from six to 10 per targeted intervention (approximately one relay agent for 100 people). The exact number of people in the team ranged from 10 to 14. The list of materials used for implementation of interventions in the target areas can be found in the online repository. 22

Data collection and analysis
We used a cross-sectional study design to describe the case-area targeted interventions, their coverage and potential effects. Data sources included: (i) the patient list for those admitted to healthcare facilities; (ii) the household contact list held by the intervention team; and (iii) the data collected within the target area by the intervention team, including coverage of interventions. Intervention coverage was estimated as the proportion of people and households who received the interventions within a given target-area radius. The main variables and outcomes were: promptness of the response; the proportion of people or households who received the interventions (health education, vaccination, antibiotic chemoprophylaxis and point-of-use water treatment); and the incidence of cholera in the target areas over time. A trained epidemiologist supervised the data collection. Data were entered into tablets using Kobo software (Kobo Inc., Toronto, Canada) to reduce the potential for errors.
For the analysis, we expressed continuous variables as means and simple ranges and summarized categorical variables (coverage) as counts and percentages. We constructed an epidemic curve to visualize the incidence of cases and timeline of interventions. We compiled the direct and indirect costs of the intervention (human resources, equipment and vaccines). We used Microsoft Excel

Ethical considerations
Case-area targeted interventions were validated as complementary interventions to cholera control by the Department for the Control of Disease, Epidemics and Pandemics of the Cameroon Ministry of Public Health. Administrative clearance was obtained from local authorities. All families who took part in this intervention gave verbal consent. Only aggregated data collected for programmatic purposes were used for this analysis and no individual-level patient data were used.

Results
Through active case-finding in the Kribi health area, nine cases of cholera were identified by rapid diagnostic testing (including one death in the community). These cases triggered implementation of eight case-area targeted interventions in seven neighbourhoods of four health areas of the Kribi district over 1 month ( Table 1). Contacts of one index case could not be traced, therefore interventions could not be implemented for that person. Most interventions were in urban settings (five out of eight) and one intervention took place at the central prison. The average time between case detection and complete implementation of the interventions was 3.4 days (range: 1.0-7.0). On average, an area covered in a targeted intervention had a radius of about 150 m (range: 100-250), covering from seven to 544 households and seven to 1687 individuals (Table 1), depending on the population density. The average number of people per household was 3.8 (range: 1.0-12.6).

Clinical characteristics
The mean age of the eight people with cholera was 25 years (range: 6 weeks to 66 years) and five of them were male. One in two individuals had a positive stool culture for V. cholerae. The strain most commonly identified through culture was V. cholerae serotype O1 (four out of eight people). Among the index cases, resistance for doxycycline was identified in one out of four people tested and no resistance for azithromycin was reported. Five out of eight people had severe dehydration (Table 2). Overall, 1685 people were vaccinated in five of eight communities where targeted interventions were implemented. The highest proportion of people were immunized at the central prison (314/377 people, 83.3%), followed by Mokolo community (509/1054 people, 46.4%). Vaccines were not administered to the last three targeted interventions in Damakale, Mbeka'a Paris and Village 7 because of vaccine shortages. Across all sites, 86.2% of households (1322/1533 households) were reached by health promotion, ranging from 76.1% (86/113 households) in Wamié to 100.0% (30/30 households) in the central prison. All households reached received chlorine tablets and soap bars. A total of 18 824 packs of chlorine tablets was distributed, especially in the communities of Mokolo (4400 packs) and Petit Paris (6992 packs). The highest number of people receiving antibiotics as prophylaxis were at the central prison (73 people), Damakale (seven people) and Village 7 (seven people; Table 3).

Response times
Across all targeted interventions, the average time elapsed from the onset of symptoms to admission of a person with suspected cholera was 1.0 day (range: 1.0-2.0). All suspected cholera patients admitted to a health facility had their rapid diagnostic test results within 1 hour. The average time between the rapid diagnostic test result and the launch of interventions was 3.4 days (range: 0.5 to 6.0 days). On average it took 1.5 days (range: 1.0-3.0) for all the components of the interventions to be completed in a target area.

Vaccination coverage
Oral cholera vaccination was possible in five of the eight targeted interventions. The percentage of people newly vaccinated in the target areas ranged from 12.6% (204/1613 people) in Petit Paris to 83.0% (313/377 people) at the central prison (

Epidemic curve
As shown in Fig. 1, implementation of targeted interventions during week 38 was followed by a decrease in the number of cases and a flattening of the curve at week 42. Interventions were stopped when no further rapid diagnostic testconfirmed cases were reported. Localized cholera interventions, Cameroon Jean Patrick Ouamba et al.

Discussion
We found that it was feasible to implement case-area targeted interventions in a timely way at the tail-end of a cholera epidemic in Kribi district. The interventions were effective at boosting vaccination coverage in the target populations at risk in Kribi, delivering water, sanitation and hygiene interventions to people living in the neighbourhood and providing chemoprophylaxis to people most at risk. Targeted interventions also provided timely opportunities for active case-finding in the community and referrals for management. Although we could not establish the effect of targeted interventions on cholera incidence, we believe that the rapid implementation of targeted interventions contributed to the rapid decrease in transmission and containment of the outbreak. After the end of the study, no further cases were reported in Kribi up until week 49 of 2021.
Despite its originality, implementation of case-area targeted interventions come with several field challenges, including increased cost and promptness of actions which require robust coordination and collaboration. In addition to the limited supply of oral cholera vaccine and some people's hesitancy to be vaccinated, the availability of the resources necessary for the interventions was a major limitation. In Kribi, targeted interventions were launched without availability of water, sanitation and hygiene items such as chlorine tablets; these were later made available by the United Nations Children's Fund (UNICEF). Additionally, surveillance may have not detected some cases. Targeted interventions were clustered around cases and conducted in a relatively small area with adequate personnel, which may not reflect many settings where cholera outbreaks happen. Lastly, In previous implementations, an association was observed between the promptness of initiating case-area targeted interventions and length of cholera outbreaks. Prompt targeted interventions were effective in shortening cholera epidemics in Haiti. 10 In Kribi, apart from the first interventions performed on the seventh day after identification of a cholera case, all other targeted interventions were started within a period of less than 7 days. We benefited from an ongoing study on the performance of rapid diagnostic tests, which allowed for easy access to enriched rapid diagnostic tests, thus enabling rapid case detection and confirmation by culture. However, promptness of case presentation, outbreak detection, investigation and response are challenging during cholera outbreaks. In a meta-analysis of cholera outbreaks, the median delay between detection and response was 10 days (interquartile range: 7-18). 24 Although there has been success in Haiti and Yemen, 10,25 interventions teams can rapidly become overwhelmed and resources become depleted as small outbreaks progress to large outbreaks. 10,12 For these reasons, targeted interventions appear to be less demanding when implemented at the end of an outbreak 10,12 (as seen here in Kribi and in Juba in South Sudan 13 ) but also promptly before the outbreak gets too large.
The choice of the radius for targeted interventions determines the efficacy of the interventions. A modelling study of 4352 reported cases in Chad over 232 days found that cholera cases were reduced by 81% and the length of cholera epidemics reduced by 63% when interventions were implemented with oral cholera vaccination and within a 100 m radius of index cases. 10 In our settings, the choice of the radius for targeted interventions was based on the setting (rural or urban) and the density of households. The majority of interventions (five out of eight) were performed in the urban area of Kribi, which made implementation easier. In crowded areas such as the central prison, everyone in the vicinity of cases were included in the intervention due to concerns about equity, raising the radius of intervention to 250 m. In less crowded areas, the radius was also increased to 250 m maximum. Damakale had fewer people included in the interventions because it  is a village with scattered households, with an average of one household within a radius of 100-250 m, even up to 1 km from the index case.
Several authors have described the added value of including oral cholera vaccination in case-area targeted interventions. 11,13,25,26 Vaccination as part of targeted interventions increased oral cholera vaccination coverage in our setting, especially in the slums of Mokolo, in Afan Mabe and at the central prison of Kribi. Here, surplus doses of oral cholera vaccine obtained from the global stockpile for a mass vaccination campaign, were made available by the health ministry. Due to vaccine shortages, oral cholera vaccination was possible in only five out of eight targeted interventions, with poor coverage in the Petit Paris area. Unfortunately, the global oral cholera vaccine stockpile only has mechanisms to obtain oral cholera vaccine for preventive and reactive mass vaccination campaigns but not for case-area targeted interventions. 27 Médecins Sans Frontières and other organizations thus rely on obtaining their own supply of oral cholera vaccine for targeted interventions. 28 In the context of the COVID-19 pandemic, there has been growing concerns about vaccine safety among the public. 29 Although we did not collect data on vaccine hesitancy in a formal way, anecdotally some people were reluctant to receive oral vaccine or antibiotic prophylaxis. The reasons for refusal were most often associated with the fear that this would be a strategy to escalate COVID-19 transmission. However, these people were accepting of the distribution of soap bars and chlorine tablets. Given the limited stocks, the distribution of water storage cans was based on household assessment.
Full packages of case-area targeted interventions include antibiotics used for prophylaxis of close household contacts. 10,30 However, due to concerns about emergence of resistant V. cholerae strains, 31,32 the Global Task Force on Cholera Control only recommends selective antibiotic chemoprophylaxis for closed populations at high risk of infection (such as prisons) and not community-wide chemoprophylaxis. 22 For these reasons, in our settings, chemoprophylaxis was done in the central prison and reserved for close contacts in the primary households who had not previously received a dose of oral cholera vaccine. In addition to protecting unvaccinated close contacts, antibiotics may also have an important role in quickly protecting individuals from infection since they act faster than oral cholera vaccine. 15 Implementation of targeted interventions in Kribi was supported by Médecins Sans Frontières, who covered the expenses related to human resources and physical resources (excluding chlorine tablets). The total cost of the intervention was 23 000 United States dollars. However, this amount was not the actual cost as some items were provided by Médecins Sans Frontières including drugs, rapid diagnostic tests, boots, vehicles, fuel and tablets. With good coordination among stakeholders, targeted interventions can be easily replicated in low-resource settings especially at the beginning or at the end of an outbreak, thereby minimizing the cost. In Cameroon, the health ministry has led individual targeted interventions in three other regions during the ongoing outbreak in 2022, with the support of partners. The main challenges to scaling-up interventions in each region include ensuring widespread availability of rapid diagnostic tests, vaccines and funds; achieving timely deployment of interventions; and instituting decentralized and sustainable systems.
Our experience shows that, despite some challenges, a full package of targeted interventions with oral cholera vaccination could be promptly implemented at the tail-end of a cholera outbreak. Despite limited evidence, targeted interventions seem to be a promising alternative strategy in the cholera control toolkit. For smooth implementation of targeted interventions during subsequent cholera epidemics worldwide, we recommend scaling-up the availability of single-dose oral cholera vaccination, antibiotics and water, sanitation and hygiene items. Our study should stimulate deeper investigations of the effectiveness of case-area targeted interventions throughout the cycle of cholera outbreaks. ■